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Background: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult‐onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. Objective: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. Methods: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing. Results: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG‐PET demonstrated brain hypometabolism and [11C]Flumazenil‐PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls. Conclusions: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations. [ABSTRACT FROM AUTHOR]

The crack initiation life of a ductile additively manufactured nickel‐based superalloy is studied and modeled for low‐cycle fatigue and thermomechanical fatigue conditions up to 600°C. Isothermal experiments were performed on smooth specimens at temperatures up to 600°C with different applied strain ranges. Additionally, thermomechanical fatigue experiments at 100–450°C and 100–600°C were performed on smooth specimens under in‐phase and out‐of‐phase conditions. A life prediction model accounting for the anisotropy was developed, where the temperature cycle is accounted with a ΔT‐functionality, generating good agreements with the experiments. The model was also validated on notched specimens undergoing thermomechanical fatigue conditions at 100–500°C using simplified notch correction methods. Highlights: The fatigue crack initiation life of an additive manufacturing (AM) combustor alloy was studied.Isothermal and anisothermal conditions up to 600°C were studied.The life prediction model accounts for the anisotropic behavior.Dependence of Tmax and ΔT was used for the life prediction constants.The model predicts the experimental life with good agreement. [ABSTRACT FROM AUTHOR]

Summary: There is a risk of a building suffering unsustainable structural damage in the event of a large fire. Therefore, it is necessary to design buildings to withstand expected fires. A widely used simplified calculation method is the so‐called 'time‐equivalence' method. There are significant concerns about the suitability of this method. This paper is Part I of a twofold study examining the state of the art of time‐equivalence methods. The purpose of this paper is to provide a detailed background of the development of time‐equivalence methods since its first introduction in 1928 and to provide an initial high‐level assessment of the accuracy of these methods. A simple scoring system is used to assess the methods based on the accuracy of the analysis techniques used in their derivation. The study revealed that most methods do not account well for structural system response to fire exposure. While some time‐equivalence methods do yield accurate results, further analysis is required to fully assess their suitability. [ABSTRACT FROM AUTHOR]

Summary: There is a risk of a building suffering unsustainable structural damage in the event of a large fire. Therefore, it is necessary to design buildings to withstand expected fires. A widely used simplified calculation method is the so‐called "time‐equivalence" method. There are significant concerns about the suitability of this method. This paper is part II of a twofold study examining the state of the art of time‐equivalence methods. The purpose of this paper is to identify methods and/or analysis concepts which show the potential for use in modern design. A SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis is used for this purpose. However, as there is a large number of time‐equivalence methods to assess, a numerical case study is first undertaken to identify methods which have sufficient accuracy to warrant further study. These analyses found that, while none of the time‐equivalence methods studied have sufficient accuracy for use in their present form, the methods derived using the equal energy concept provide a good basis to model the effects of fire on a structure. This study recommends that a new time‐equivalence method be developed using the equal energy approach. [ABSTRACT FROM AUTHOR]

Summary The use of virtual reality in human behavior in fire research has the advantage of being able to produce results comparable to more traditional laboratory or field experiments. This method relies not only on the technology employed but also on the participants' perception of realism when exposed to a virtual emergency scenario. A virtual scenario can be perceived as realistic based on the way it looks and on the way objects in it operates. However, in some experiments, behavioral realism can be the most relevant feature to obtain meaningful results. In this article, knowledge gained by running four different virtual reality experiments is presented in the form of challenges and recommendations to enhance the realism of the virtual experience. Although not in a comprehensive way, these challenges and recommendations refer to different parts of the process of running a virtual reality experiment for research in human behavior in fire, from the design of the environment to the behavior of the participants in it. The recommendations provided are based on observations. By spreading this knowledge, it is expected to aid the broader fire safety engineering community to develop more realistic virtual reality experiments for data collection on human behavior in fire. [ABSTRACT FROM AUTHOR]

Summary: Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells. [ABSTRACT FROM AUTHOR]

Summary: Crowd movement simulation models are generally based on aggregated speed and flow data collected more than 50 years ago. There appears to be no validated modelling capability to include the impact of recent and future changes in population demographics, resulting from an ageing population and increasing obesity rates. New analytical approaches and data gathering are required to successfully model crowd movement and safety for current and future generations. This study carried out (a) a review of the primary components of crowd movement, demographics and analytical techniques, (b) prototype experiments to investigate age‐related aspects of space and potential points of contact and (c) a new predictive model for crowd flow analysis based on pedestrian biomechanics and anthropometric data. The model uses the physical space taken up by the biomechanical walking process and the spatial buffer between points of potential contact with other pedestrians to predict the speed of movement at different levels of congestion. The new analytical model was used to predict single file speeds (for people with different demographics in congested space), which compared well with published experimental data. The next steps for model development for wider "flows" and additional experiments to provide data sets for wider demographics are also proposed. [ABSTRACT FROM AUTHOR]

This article emphasizes the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high‐intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereo‐electroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; (c) addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high case load, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open‐loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering the acoustic energy, further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap. [ABSTRACT FROM AUTHOR]

We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14. [ABSTRACT FROM AUTHOR]

Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal. [ABSTRACT FROM AUTHOR]

The egress strategy in high-rise buildings has traditionally been based on the sole use of stairs for evacuation. However, it is becoming more common to include evacuation elevators in the egress strategy in high-rise buildings. Traditionally, evacuation elevators have not been allowed as an evacuation route, and people have been instructed to not use elevators in case of fire. This means that people might still not consider evacuation elevators even if they are designed to be safe in case of fire. Even if people choose evacuation elevators, they might not be willing to wait very long for an elevator to arrive. Virtual reality (VR) experiments were conducted to study exit choice and the waiting time for evacuation elevators in high-rise buildings. The experiment was performed in a VR lab with a VR model of an existing high-rise building. Results suggest that a simple way-finding system using green flashing lights can influence people to more likely choose the elevator as their first evacuation choice. The results also show that the general trend is that people wait for either a limited time (<5 min) or a long time (>20 min). Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this work we employ terahertz (THz) ellipsometry to determine two-dimensional electron gas (2DEG) density, mobility and effective mass in AlGaN/GaN high electron mobility transistor structures grown on 4H-SiC substrates. The effect of the GaN interface exposure to low-flow-rate trimethylaluminum(TMA) on the 2DEG properties is studied. The 2DEGeffectivemass and sheet density are determined to be in the range of 0.30-0.32m0 and 4.3-5.5 x 1012 cm-2, respectively. The 2DEG effective mass parameters are found to be higher than the bulk effective mass of GaN, which is discussed in view of 2DEG confinement. It is shown that exposure to TMA flow improves the 2DEG mobility from 2000 cm²/Vs to values above 2200 cm²/Vs. A record mobility of 2332±61 cm²/Vs is determined for the sample with GaN interface exposed to TMA for 30 s. This improvement in mobility is suggested to be due to AlGaN/GaN interface sharpening causing the reduction of interface roughness scattering of electrons in the 2DEG. [ABSTRACT FROM AUTHOR]

SUMMARY In fire safety engineering, information about the expected walking speed of occupants through smoke is often one factor that is of interest to the designer. However, despite the fact that research already in the 1970s demonstrated that people tend to evacuate through smoke, little research has been performed on the topic since, and evidently, there is a lack of data on walking speed in smoke. This has created a situation where fire safety engineering assessments of the required safe escape time may be intimately associated with high uncertainties, especially for buildings in which people can be expected to evacuate long distances through smoke, for example, underground transportation systems. In order to address the lack of data on movement through smoke, 133 data points on individual walking speed in smoke are presented in this paper. The data lie within an extinction coefficient range of 1.2-7.5 m−1. In line with previous studies, it is demonstrated that the level of smoke density has a negative impact on the walking speed, whereas no significant effects of inclination, type of floor material, gender, age and height could be found in the data. In this paper, recommendations are also provided on how designers should treat the data in their fire safety risk assessments, depending on the type of risk analysis method, that is, if the designer is performing a deterministic analysis or a quantitative risk analysis. It is argued that this information can be used to reduce the uncertainty in future risk analyses involving egress calculations. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit ( MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease. [ABSTRACT FROM AUTHOR]

A Ronchi interferometer for hard X-rays is reported in order to characterize the performance of the nanofocusing optics as well as the beamline stability. Characteristic interference fringes yield qualitative data on present aberrations in the optics. Moreover, the visibility of the fringes on the detector gives information on the degree of spatial coherence in the beamline. This enables the possibility to detect sources of instabilities in the beamline like vibrations of components or temperature drift. Examples are shown for two different nanofocusing hard X-ray optics: a compound refractive lens and a zone plate. [ABSTRACT FROM AUTHOR]

The heartworm Dirofilaria immitis is an important parasite of dogs. Transmitted by mosquitoes in warmer climatic zones, it is spreading across southern Europe and the Americas at an alarming pace. There is no vaccine, and chemotherapy is prone to complications. To learn more about this parasite, we have sequenced the genomes of D. immitis and its endosymbiont Wolbachia. We predict 10,179 protein coding genes in the 84.2 Mb of the nuclear genome, and 823 genes in the 0.9-Mb Wolbachia genome. The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States. The differential presence of anabolic pathways such as heme and nucleotide biosynthesis hints at the intricate metabolic interrelationship between the heartworm and Wolbachia. Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates. This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness. [ABSTRACT FROM AUTHOR]

Foramen ovale electrodes (FOEs) can localize the epileptogenic zone in adults with mesial temporal lobe epilepsy (TLE). Our aim was to investigate the feasibility and safety of using FOEs to investigate refractory TLE in children. Thirty-eight children with seizure semiology and video-EEG (electroencephalography) consistent with medically refractory TLE, and/or the presence of a lesion in the temporal lobe, had FOEs inserted. Complications occurring during the monitoring and up to 3 months after surgery and the long-term seizure outcome were registered. Forty electrodes were placed in 38 patients. The mean age of the patients was 9.8 years (range 2.3–15.4 years). FOEs confirmed a unilateral mesial temporal lobe seizure onset in 14 patients, onset in both FOEs and lateral electrodes in two patients, and onset in the anterior temporal electrodes in only one patient. Six patients had seizures recorded but were not considered surgical candidates; four patients had no seizures recorded, and 11 patients were further investigated with depth electrodes. One patient (2.6%) developed a hematoma in the cheek, and in two patients the electrodes were extracranial but could still be used for recording. Twenty-eight children had a temporal resection; 25 were Engel class I at follow-up. FOEs are safe to use in children and provide valuable information on the mesial temporal lobe structures in the preoperative investigation of pediatric TLE. Patient selection for FOE investigation is, however, essential for a conclusive result. [ABSTRACT FROM AUTHOR]

Different virtual reality (VR) experimental tools and equipment are available for evacuation research, ranging from highly immersive systems such as cave automatic virtual environments (CAVEs) to head‐mounted displays (HMDs). In particular, mobile‐powered HMDs are an extremely cost‐efficient solution, for which the research potential for evacuation studies needs to be assessed. This study compares the results of tunnel evacuation experiments aimed at investigating the design of flashing lights on emergency exit portals using two different VR methods (CAVE vs. mobile‐powered HMD). The experiments were performed by repeating the same case study in a CAVE laboratory and a low‐cost mobile‐powered HMD. The CAVE experiment involved 96 participants, whereas the HMD experiment involved 55 participants. An affordance‐based questionnaire was used to interview participants immersed in a VR road tunnel emergency evacuation scenario and rank different emergency portal designs. Questionnaire results show consistency between the two experimental methods for the variables investigated, thus leading to be in favor of the use of low‐cost mobile‐powered HMD tools in evacuation scenarios with a relatively limited level of complexity. [ABSTRACT FROM AUTHOR]

Background: The bladder exstrophy‐epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods: We performed array comparative genomic hybridization (array‐CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation. [ABSTRACT FROM AUTHOR]

Foxc2 is one of the earliest podocyte markers during glomerular development. To circumvent embryonic lethal effects of global deletion of Foxc2, and to specifically investigate the role of Foxc2 in podocytes, we generated mice with a podocyte‐specific Foxc2 deletion. Mice carrying the homozygous deletion developed early proteinuria which progressed rapidly into end stage kidney failure and death around postnatal day 10. Conditional loss of Foxc2 in podocytes caused typical characteristics of podocyte injury, such as podocyte foot process effacement and podocyte microvillus transformation, probably caused by disruption of the slit diaphragm. These effects were accompanied by a redistribution of several proteins known to be necessary for correct podocyte structure. One target gene that showed reduced glomerular expression was Nrp1, the gene encoding neuropilin 1, a protein that has been linked to diabetic nephropathy and proteinuria. We could show that NRP1 was regulated by Foxc2 in vitro, but podocyte‐specific ablation of Nrp1 in mice did not generate any phenotype in terms of proteinuria, suggesting that the gene might have more important roles in endothelial cells than in podocytes. Taken together, this study highlights a critical role for Foxc2 as an important gene for podocyte function. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Genomic screening in rare disorders: New mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability, by Malin Kvarnung et al., https://doi.org/10.1111/cge.13448. The cover image is based on the Original Article Genomic screening in rare disorders: New mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability, by Malin Kvarnung et al., https://doi.org/10.1111/cge.13448. [ABSTRACT FROM AUTHOR]

Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelination disorder, characterized by significant developmental delay, truncal hypotonia, spasticity, dysarthria, and nystagmus. Conventional magnetic resonance (MR) images demonstrate discordance of myelin maturation, while newer MR techniques, such as MR spectroscopy and diffusion tensor imaging, may be helpful in disease assessment. We report on a family of two young boys and their mother who share the same unusual 4-bp deletion of the PLP1 gene: c51&#95;54 del TTCC, causing truncation of the PLP1 in exon 2. The brain MRI appearances in this unique deletion, using newer MR imaging, are described., ((c) 2010 Wiley-Liss, Inc.)